The SIRPa-CD47 immune checkpoint in NK cells

Natural killer (NK) cell activation depends on the balance of expression and signaling through stimulatory versus inhibitory receptors. According to the 'missing-self' hypothesis, lack of target cell major histocompatibility complex (MHC) class I expression facilitates NK cell-mediated cytotoxicity. Here we describe an NK cell immune checkpoint that becomes effective when supra-normal CD47 expression engages with signal regulatory protein-a (SIRPa) on activated NK cells. In mice and humans, lentiviral vector-induced species-specific CD47 overexpression in MHC class I and II-deficient target cells efficiently prevents NK cell-mediated killing, but it does not prevent cross-species NK cell-mediated killing. Overexpression of rhesus monkey CD47 in human MHC-deficient cells prevented cytotoxicity by rhesus NK cells in a xenogeneic setting. This immune checkpoint is similarly active in macrophages and also prevents MHC-deficient cells overexpressing CD47 from macrophage clearance. CD47 may thus be an effective checkpoint enhancer easily inducible with gene editing to develop engineered cell products that are resistant against NK cell-mediated killing.